Neuropsychiatric disorders are economically and socially devastating. For example, schizophrenia is the 8th leading cause of disability worldwide with a lifetime prevalence of 0.6 to 1.3% characterized by high morbidity and mortality. Only less than 15% of people with this disability are competitively employed, whilst about 20% live independently. Less than 50% will marry or have a long-term intimate partner.
The domains of pathology in schizophrenia are positive symptoms (delusions, hallucinations, disorganized thoughts and speech, disorganized or bizarre behaviour), negative symptoms (anhedonia, anergia, affective flattening, alogia, avolition-apathy), affective symptoms (dysphoria, hopelessness, suicidality, anxiety, hostility, aggression) and cognitive deficits (speed of information processing, attention, concentration, executive functions, new learning and memory).
The primary effect of first generation antipsychotics is dopamine (D2 receptor) blockade. These are effective in treating positive treatments but minimally effective in treating negative symptoms with common side effects including extrapyramidal symptoms and tardive dyskinesia. The second generation antipsychotics have a lower affinity for dopamine D2 receptors but a higher affinity for serotonin (5HT 1A, 2A, 2C, 3, 6, 7) and nor-epinephrine (α1 and α2) receptors. While these are effective in treating the positive symptoms of schizophrenia, they exert modest effects on negative symptoms and cognitive deficits. Thus, despite the availability of some drugs for treating neuropsychiatric disorders such as schizophrenia, there are many unmet needs for improved methods and compounds for treating neuropsychiatric disorders.